One of the major mediators of intercellular communication is exosomes [Martins et al., 2013]. Exosomes are 30-100 nm nanovesicles responsible for the transport of a myriad of molecular cargo including protein, lipids, mRNA and miRNA [Valadi et al., 2007]. Exosome signaling is linked to a number of pathologies including cancer [Martins et al., 2013; Jung et al., 2009], neurological disorders [Rajendran et al., 2006], and cardiovascular disease [Hergenreider et al., 2012]. For example, local and distal communication between tumor and supporting cells is critical for tumor progression [Peinado et al., 2012; Ghajar et al., 2013].
Because of their role in disease progression and inherent targeting properties there is significant interest in exosome production, detection, and manipulation of their molecular content [Katakowski et al. 2013; Rana et al. 2012]. For example, isolated cells have been engineered to overexpress certain potentially therapeutic cargoes that can be packaged into secreted exosomes whereupon the exosomes are then systemically delivered as a therapeutic [Johnsen et al. 2014]. In addition, dendritic cells have been shown to process antigens ex vivo that are then presented on the surface of secreted exosomes, which can then be isolated and systemically delivered to stimulate favorable anti-tumor immune responses [Zitvogel et al. 1998]. Also, exosomes can first be isolated, and then tailored to incorporate certain therapeutic or enhanced targeting molecules using a number of techniques [Johnsen et al. 2014]. However, these methods have significant limitations for in vivo applications and variability with regard to cargo loading [Johnsen et al. 2014].
The cell membrane has a critical role in intercellular communication because the cell membrane is the interface between individual cells and their external environment. A number of critical cellular events, including signal transduction, membrane compartmentalization and endosomal trafficking, are coordinated in lipid rafts. Lipid rafts are complex membrane domain structures that are characterized by an excess of cholesterol, sphingolipids, and proteins [Lingwood et al. 2010; Simons et al. 2010]. Scavenger receptor type B-1 (SR-B1) is one of the many receptors that are expressed in lipid rafts [Umemoto et al. 2013]. Because of this, tumor progression is often associated with an increased expression of SR-B1 aiding in the procurement of cholesterol needed for maintaining cell membrane integrity and other cellular processes [Gabitova et al. 2014]. Beyond cholesterol metabolism, modulating lipid raft cholesterol content inhibits downstream second messenger signaling events such as ERK 1/2 signaling which have been reported as critical for exosome uptake. As a result, nanostructures that can change the cell membrane by associating with lipid rafts or binding receptors in the cell membrane, such as SR-B1, may be useful for therapeutic, diagnostic, or research purposes.
Synthetic nanostructures have been shown to be useful for therapeutic, diagnostic, and research purposes. For example, nanostructures having a corona of nucleic acids extending radially from the center have been shown to be useful for inhibiting gene expression (as described in International Patent Publication No. WO/2006/6138145 entitled “Nucleic acid functionalized nanoparticles for therapeutic applications,” filed 8 Jun. 2006), nanostructures having a detectable marker have be shown to be useful for detecting intracellular targets in living cells (as described in International Patent Publication No. WO/2008/098248 entitled “Particles for detecting intracellular targets,” filed 11 Feb. 2008), and nanostructures having the size, shape, surface chemical composition, and cholesterol binding properties of natural, mature spherical HDL have been shown to be useful for sequestering cholesterol for the treatment of diseases or conditions involving abnormal lipid levels or cholesterol metabolism (as described in International Patent Publication No. WO/2009/131704 entitled, “Nanostructures suitable for sequestering cholesterol and other molecules,” filed 24 Apr. 2009 and International Patent Publication No. WO/2013/126776 entitled, “Nanostructures for treating cancers and other conditions,” filed 22 Feb. 2013), all publications incorporated herein by reference in its entirety for all purposes. Although International Patent Publication No. WO/2009/131704 describes the use of nanostructures for treating cancers generally and International Patent Publication No. WO/2013/126776 describes the use of nanostructure for treating cancer cells having an SR-B1 receptor, neither publication describes the use of nanostructures to modulate or monitor intercellular communication. Although it was known that SR-B1 could bind synthetic nanostructures and that the binding of the nanostructures may lead to apoptosis of certain cell types, e.g. lymphoma, it was not known that SR-B1 binding of a nanostructure in a viable cell would exhibit modulated intercellular communication. It was unexpected, therefore, that nanostructures such as those described herein could be used for the treatment, diagnosis, or research of vesicle-mediated diseases, as the role of these particles in modulating vesicle uptake or release was not envisioned.
To improve upon current methods, there exists a need for in the art for nanostructures useful for the treatment and diagnosis of vesicle-mediated diseases and conditions and for research in intercellular communication processes generally. Inhibiting intercellular communication may be effective for slowing or halting vesicle-mediated diseases. Moreover, nanostructures that can associate with vesicles may be able to be specifically delivered to specific sites for therapeutic, diagnostic, or research purposes.